DESCRIPTION (adapted from the application) The candidate is an MD/PhD graduate of the Cornell/Rockefeller MSTP program. She has completed anatomic pathology residency training at Yale, including postdoctoral research in cell/molecular biology. She seeks support for full-time mentored research, with access to resources of both Internal Medicine/Digestive Disease and Pathology Departments at Yale, that would launch her as an independent academic pathologist studying epithelial cell polarity and growth regulation in the gastrointestinal system. Her long-term research goal is to understand the role of CASK, a MAGUK-family scaffolding protein, in the assembly, organization, and function of signal transduction complexes at the epithelial basolateral membrane. MAGUKs (membrane-associated guanylate kinases) are cytoplasmic scaffolding molecules that organize protein complexes at specialized membrane regions. In epithelia, they have been implicated in tumor suppression (Drosophila discslarge, d1g) and targeting of growth factor receptors to the basolateral membrane (C. elegans LIN-2). We previously cloned hCASK, the human homologue of C. elegans LIN-2, and showed that it binds syndecan, a co-receptor for basic fibroblast growth factor (bFGF). We recently found that hCASK also binds a different MAGUK, hDIg, (human homologue of d1g tumor suppressor) in human intestinal cells in vivo. Our aims are (1) to further characterize the hCASK-hDlg interaction in vivo and test several potential mechanisms of its regulation; (2) to investigate the hCASK-syndecan interaction in cultured cells, and to test for associations with an epithelial-specific FGF signaling pathway and with other epithelial MAGUKs; and (3) to assay the function of CASK in vivo by generating tissue-specific knockout mice in which the CASK gene has been deleted in epithelial cells of the urinary tract and intestine. The latter will be accomplished by breeding transgenic mouse strains obtained from other laboratories. We anticipate these studies will shed considerable light on the molecular interactions of CASK, its role in growth factor complex assembly and/or signal transduction, and its potential involvement in tumorigenesis.